London S J, Daly A K, Leathart J B, Navidi W C, Carpenter C C, Idle J R
National Institute of Environmental Health Services, Research Triangle Park, NC 27709, USA.
Carcinogenesis. 1997 Jun;18(6):1203-14. doi: 10.1093/carcin/18.6.1203.
The well described genetic polymorphism of the CYP2D6 gene influences response to a wide variety of therapeutic agents metabolized by the CYP2D6 enzyme product. CYP2D6 also appears to play a role, along with other cytochrome P450 enzymes, in the metabolic activation of the tobacco specific nitrosamine, NNK, as well as metabolism of nicotine to cotinine. While impaired activity of CYP2D6 was strongly protective against lung cancer in some studies, primarily based on phenotyping, the literature is conflicting. The molecular basis of CYP2D6 deficiency is now well understood, enabling the use of genotyping to classify individuals. We therefore examined whether lung cancer risk is reduced by the presence of four CYP2D6 alleles associated with impaired activity due to an inactivating mutation--CYP2D64, CYP2D63, CYP2D65 and CYP2D616--among 341 incident cases of lung cancer and 710 population controls of Caucasian or African-American ethnicity in Los Angeles County, California. We did not confirm a strong association between the presence of these inactivating alleles and lung cancer risk [odds ratio (OR) = 0.90, 95% confidence interval (CI) 0.60-1.35 for Caucasians], although there was a small decreased risk among the African-Americans (OR = 0.66, 95% CI 0.38-1.14). Among smokers, when the data are stratified according to lifetime smoking history, there is a suggestion of an association limited to Caucasian smokers of <35 pack-years, the median for all smokers in these data (OR = 0.49, 95% CI 0.23-1.04). However, among African-American smokers, who smoke less than Caucasians, the association did not differ between smoking categories. We also examined the possible role of additional copies of the CYP2D6 gene, which lead to enhanced CYP2D6 activity, in increasing lung cancer risk. Among controls the prevalence of having more than two copies of the CYP2D6 gene and no inactivating alleles was 4.3% for Caucasians and 4.9% for African-Americans. Relative to subjects with an inactivating allele, those with an additional copy of the CYP2D6 gene and no inactivating alleles may be at increased risk of lung cancer, particularly for adenocarcinoma (OR = 3.61, 95% CI 1.08-11.7 for African-Americans and OR = 2.20, 95% CI 0.69-6.0 for Caucasians). Our data suggest that the CYP2D6 genetic polymorphism is not the strong risk factor for lung cancer suggested by some studies of phenotype, but may play a minor role.
细胞色素P450 2D6（CYP2D6）基因中广为人知的基因多态性会影响对多种由CYP2D6酶产物代谢的治疗药物的反应。CYP2D6似乎还与其他细胞色素P450酶一起，在烟草特异性亚硝胺NNK的代谢活化以及尼古丁向可替宁的代谢过程中发挥作用。虽然在一些主要基于表型分析的研究中，CYP2D6活性受损对肺癌具有很强的保护作用，但文献报道存在矛盾。目前已经很好地理解了CYP2D6缺乏的分子基础，这使得能够利用基因分型对个体进行分类。因此，我们在加利福尼亚州洛杉矶县的341例肺癌新发病例和710名白种人或非裔美国人种族的人群对照中，研究了因失活突变而与活性受损相关的四个CYP2D6等位基因——CYP2D64、CYP2D63、CYP2D65和CYP2D616——的存在是否会降低肺癌风险。我们没有证实这些失活等位基因的存在与肺癌风险之间存在强关联[白种人的优势比（OR）=0.90，95%置信区间（CI）为0.60 - 1.35]，尽管非裔美国人的风险略有降低（OR = 0.66，95%CI为0.38 - 1.14）。在吸烟者中，当根据终生吸烟史对数据进行分层时，仅在吸烟量<35包年的白种吸烟者中存在关联迹象，这是这些数据中所有吸烟者的中位数（OR = 0.49，95%CI为0.23 - 1.04）。然而，在吸烟量少于白种人的非裔美国吸烟者中，不同吸烟类别之间的关联没有差异。我们还研究了导致CYP2D6活性增强的CYP2D6基因额外拷贝在增加肺癌风险方面的可能作用。在对照人群中，拥有超过两个拷贝的CYP2D6基因且无失活等位基因的白种人的患病率为4.3%，非裔美国人的患病率为4.9%。相对于具有失活等位基因的受试者，具有一个额外拷贝的CYP2D6基因且无失活等位基因的受试者可能患肺癌的风险增加，尤其是腺癌（非裔美国人的OR = 3.61，95%CI为1.08 - 11.7；白种人的OR = 2.20，95%CI为0.69 - 6.0）。我们的数据表明，CYP2D6基因多态性并非如一些表型研究所表明的那样是肺癌的强风险因素，但可能起次要作用。
